The hair follicle is a mini-organ that is regenerated from stem cells in the adult. Significant progress has been made in defining and studying the stem cells of the follicular epithelium that regenerate the follicle. However their activation and the differentiation of their progeny to regenerate hair follicles is guided by a specialized mesenchymal population, the dermal papilla (DP). While the importance of these DP cells in follicle formation is clearly established, the nature of the signals generated by them and the ways in which they may change to guide keratinocytes through the successive tasks required to rebuild a follicle and elaborate a hair shaft remain poorly understood. This is in part because the techniques to purify DP cells and manipulate gene expression in them have lagged behind those used to study the epithelial components of the follicle. We have developed novel approaches that allow the purification in bulk of both DP cells and their immediate precursors in development. We have also developed assays to evaluate the inductive activity of these cells during follicle neogenesis. Finally we have developed methods to manipulate gene expression specifically in dermal papilla cells in the context of intact follicles. We will employ these novel reagents and techniques to identify the changes in gene expression that characterize the dermal papilla at different stages in follicle formation, regeneration, and degeneration. The function of these genes in follicle formation and cycling will be tested both in vivo and in vitro. The results of this work will have direct implications for the management of hair growth, regeneration and loss, and also for the management of severe skin wounds where the ability to regenerate cutaneous appendages remains an elusive goal. They will also have broader impact in the fields of stem cell biology and tissue engineering, not only because the hair follicle serves as an important model system in these fields, but because DP are a source of SKPs, an adult derived progenitor population that holds therapeutic promise.